Mousse composition

ABSTRACT

A pharmaceutical aerosol foam composition including an effective amount of a pharmaceutically active ingredient; an occlusive agent; an aqueous solvent; and an organic cosolvent, the pharmaceutically active ingredient being insoluble in both water and the occlusive agent; the occlusive agent being present in an amount sufficient to form an occlusive layer on the skin, in use.

The present invention provides a composition for the topicaladministration of pharmaceutical active ingredients.

Various aerosol and non-aerosol quick breaking and slow breaking foamsfor the topical delivery of pharmaceutical active ingredients are knownin the prior art. In particular, the foam composition is an aqueousemulsion system. The foam composition upon actuation produces astabilised, homogeneous, expandable foam which breaks easily with shear.A composition of this type is often referred to as an aerosol foam or“mousse”.

It is known to use mousse compositions to topically deliverpharmaceutical active ingredients. An example of such a composition isin Australian patent application 80257/87 which discloses a moussecomposition for the topical delivery of the pharmaceutically activeingredient minoxidil. However the efficiency of such systems to deliverpharmaceutically active ingredients is limited.

Moreover, the majority of topical lotions and creams known or suggestedin the prior art for delivering pharmaceutically active ingredientscontain large amounts of petrolatum or some other occlusive agent to actas a barrier over the skin. This barrier reduces the evaporation ofmoisture from the skin which leads to increased moisture in the stratumcomeum and in the epidermis and enhances the topical delivery of thepharmaceutical active ingredients.

However, in practice it would not be desirable to include such largeamounts of an occlusive agent in a mousse formulation because whendispensed the mousse formulation would be a less stable foam, and uponapplication, the occlusive agent would leave a greasy, sticky lather onthe skin which would not be considered acceptable to the consumer.

In prior art U.S. Pat. Nos. 5,002,680 and 4,981,677, there is disclosedmousse compositions that contain an occlusive agent such as petrolatum.These compositions are directed towards cosmetic purposes, and provideno disclosure on their suitability or otherwise to enhance the topicaldelivery of pharmaceutical active ingredients. Furthers in respect ofU.S. Pat. No. 4,981,677 the formulation includes a starch component. Itis accordingly not apparent that an occlusive layer would be formed.

Accordingly, it would be a significant advance in the art if a moussecomposition could be provided that enhanced the topical delivery of thepharmaceutical active ingredient while preferably still providing apharmaceutically elegant and consumer acceptable composition.

In a first aspect of the present invention there is provided apharmaceutical aerosol foam composition including an effective amount of

a pharmaceutically active ingredient

an occlusive agent

an aqueous solvent; and

an organic cosolvent;

the pharmaceutically active ingredient being insoluble in both water andthe occlusive agent;

the occlusive agent being present in an amount sufficient to form anocclusive layer on the skin, in use.

The present invention is predicated on the surprising discovery that amousse formulation with a relatively low amount of an occlusive agent isstill able to reduce trans epidermal water loss and hence in theoryincrease skin permeability to effect greater drug skin penetration whileremaining an elegant and consumer acceptable composition.

The water-insoluble pharmaceutically active ingredient may be anysuitable type. An analgesic such as capsaicin or piroxicam, antifungalsuch as clotrimazole or miconazole nitrate, antibacterial such asnitrofurazone or gramcidin, anaesthetic such as benzocaine or lidocaine,antiviral such as aciclovir or penciclovir, antipruritic such ascrotamiton or phenol, antihistamine such as chlorpheniramine ortriprolidine, xanthine such as caffeine, sex hormone such as oestradiolor testosterone, anti-inflammatory agent or corticosteroid may be used.A corticosteroid is preferred. The corticosteroids may be selected fromone or more of the group consisting of, betamethasone valerate andclobetasol propionate.

Clobetasol propionate is preferred.

The pharmaceutically active ingredient may be present in any effectiveamounts. The pharmaceutically active ingredient may be present inamounts of approximately 0.005% by weight to approximately 10% byweight, preferably approximately 0.05% to approximately 1% by weight,based on the total weight of the pharmaceutical aerosol foamcomposition.

The aerosol foam base can be made using compositions that are well knownin the art.

The pharmaceutical aerosol foam composition may further include aneffective amount of an aerosol propellant. The aerosol propellant usedin the mousse composition may be any suitable gas, such as ahydrocarbon, e.g. propane, butane, CFCs, HFCs, nitrogen or air. In apreferred embodiment the aerosol propellant is a hydrocarbon. Where theaerosol propellant is a hydrocarbon it may be present in an amount offrom approximately 2.5% to 20% by weight, preferably 2.5% to 7.5% byweight, based on the total weight of the pharmaceutical moussecomposition. The propellant may be introduced into the moussecomposition at the time of filling utilising for example a standardaerosol dispenser, e.g. a spray can arrangement.

The occlusive agent utilised in the pharmaceutical composition accordingto the present invention may be any excipient or combination thereofthat provides an occlusive layer or hydration barrier to the skin. Anocclusive layer or hydration barrier is a layer or barrier sufficient toresult in reduction in trans epidermal water loss, which results in skinhydration. Suitable occlusive agents may be selected from one or more ofthe group consisting of mineral oils and greases, long chain acids,animal fats and greases, vegetable fats and greases, water insolublepolymers and the like. In a preferred embodiment the occlusive agent ispetrolatum.

The occlusive agent is present in an amount sufficient to permit theformation of an occlusive layer or hydration barrier on the skin of thepatient. Surprisingly applicants have discovered it is possible to formsuch an occlusive layer with a relatively low amount of occlusive agent.For example the amount of occlusive agent in the mousse composition maybe up to approximately 55%, preferably approximately 40% or less byweight based on the total weight of the composition. In a preferredembodiment of the invention the amount of occlusive agent in the moussecomposition may be up to approximately 50%, more preferably fromapproximately 20 to 50% by weight.

The pharmaceutical mousse composition may further include an effectiveamount of an emulsifier and/or surfactant.

The emulsifier or surfactant may be selected from one or more of thegroup consisting of non-ionic, anionic and cationic surfactants, e.g.fatty alcohols, fatty acids and fatty acid salts thereof.

Suitable emulsifiers or surfactants include pharmaceutically acceptable,non-toxic, non-ionic, anionic and cationic surfactants. Examples ofsuitable non-ionic surfactants include glycerol fatty acid esters suchas glycerol monostearate, glycol fatty acid esters such as propyleneglycol monostearate, polyhydric alcohol fatty acid esters such aspolyethylene glycol (400) monooleate, polyoxyethylene fatty acid esterssuch as polyoxyethylene (40) stearate, polyoxyethylene fatty alcoholethers such as polyoxyethylene (20) stearyl ether, polyoxyethylenesorbitan fatty acid esters such as polyoxyethylene sorbitanmonostearate, sorbitan esters such as sorbitan monostearate, alkylglycosides such as cetearyl glucoside, fatty acid ethanolamides andtheir derivatives such as the diethanolamide of stearic acid, and thelike. Examples of suitable anionic surfactants are soaps includingalkali soaps, such as sodium, potassium and ammonium salts of aliphaticcarboxylic acids, usually fatty acids, such as sodium stearate. Organicamine soaps, also included, include organic amine salts of aliphaticcarboxylic acids, usually fatty acids, such as triethanolamine stearate.Another class of suitable soaps is the metallic soaps, salts ofpolyvalent metals and aliphatic carboxylic acids, usually fatty acids,such as aluminium stearate. Other classes of suitable anionicsurfactants include sulfated fatty acid alcohols such as sodium laurylsulfate, sulfated oils such as the sulfuric ester of ricinoleic aciddisodium salt, and sulfonated compounds such as alkyl sulfonatesincluding sodium cetane sulfonate, amide sulfonates such as sodiumN-methyl-N-oleyl laurate, sulfonated dibasic acid esters such as sodiumdioctyl sulfosuccinate, alkyl aryl sulfonates such as sodiumdodecylbenzene sulfonate, alkyl naphthalene sulfonates such a sodiumisopropyl naphthalene sulfonate, petroleum sulfonate such as arylnapthalene with alkyl substitutes. Examples of suitable cationicsurfactants include amine salts such as octadecyl ammonium chloride,quarternary ammonium compounds such as benzalkonium chloride.

Surfactants which are a mixture of sorbitan monostearate and polysorbate60 are preferred.

The emulsifier component may be present in any suitable stabilisingamount. Preferably the emulsifier component may be in an amount wherethe ratio of emulsifier component to the occlusive agent, activepharmaceutical ingredient and cosolvent is about 1:5. The emulsifiercomponent may be present in an amount of from approximately 1% to 15% byweight, preferably approximately 2.0% to 5.0% by weight, based on thetotal weight of the pharmaceutical mousse composition.

The aqueous solvent may be present in an amount of from approximately25% to 95% by weight, preferably approximately 70% to 85% by weight,based on the total weight of the pharmaceutical mousse composition.

The composition further includes an organic cosolvent. The organicsolvent may be an ester of a fatty acid for example a C12-C15 alkylbenzoate, a medium to long chain alcohol, an aromatic and/or alkylpyrollidinone, an aromatic and/or alkyl, and/or cyclic ketone, anaromatic and/or alkyl, and/or cyclic ether, substituted and/orunsubstituted single or multiple ring aromatic, straight chain and/orbranched chain and/or cyclic alkane or silicone. The organic cosolventmay be present in amounts of approximately 0.25% to 50% by weight,preferably 0.5 to 2% by weight, based on the total weight of thepharmaceutical mousse composition. Preferred organic cosolvents includeC12-C15 alkyl benzoates (FINSOLV TN) and caprylic/capric triglyceride(CRODAMOL GTCC).

The pharmaceutical mousse composition according to the present inventionmay also contain other non-essential ingredients. The composition maycontain up to 10 weight percent of conventional pharmaceuticaladjuvants. These adjuvants or additives include preservatives,stabilisers, antioxidants, pH adjusting agents, skin penetrationenhancers, and viscosity modifying agents.

EXAMPLES

The present invention will now be more fully described with reference tothe accompanying figures and examples. It should be understood that thedescription following is illustrative only and should not be taken inany way as restrictive on the generality of the foregoing description.

FIG. 1 illustrates the effect of petrolatum content on in vitroepidermal penetration of clobetasol from topical mousse formulations 72hours after application of 10 mg/cm² of formulation.

FIG. 2 illustrates the effect of petrolatum content on the rate oftransepidermal water loss (TEWL) determined on the forearm of a healthyvolunteer 30 and 120 minutes after topical application of 10 mg/cm² offormulation.

FIG. 3 illustrates relative decreases in the rate of transepidermalwater loss (TEWL) observed on the forearm of a healthy volunteer withincreasing concentrations of petrolatum in topically appliedformulations.

FIG. 4 illustrates the effect of application of a 50% petrolatum mousseformulation on the relative rate of TEWL on the forearm of healthyvolunteers (mean±SD, n=6).

Example 1 Formulations

A series of 7 pharmaceutical formulations were prepared in accordancewith the present invention. The composition of each formulation is givenin Table 1. TABLE 1 Ingredient 1 2 3 4 5 6 7 Petrolatum  10%  10%  20% 30%  30%  40%  50% Clobetasol Propionate 0.05% 0.05% 0.05% 0.05% 0.05%0.05% 0.05% Caprylic/Capric Triglyceride — — — —  10% — — Alkyl Benzoate 10%  10%  10%  10% —  10%  10% Cetearyl glucoside 2.5% — — — — — —Sorbitan Stearate — 1.63% 2.54% 3.44% 3.02% 4.35% 5.25% Polysorbate 60 —2.37% 3.46% 4.56% 4.98% 5.65% 6.75% Water 72.25%  70.95%  58.95% 46.95%  46.95%  34.95%  22.95%  Preservatives 0.2% — — — — — —Propellent  5%   5%   5%   5%   5%   5%   5%

Example 2 Effect of Petrolatum Concentration on the In-vitro EpidermalPenetration of Clobetasol from Topical Mousse Formulations

Alm

The aim of the study was to:

-   -   (1) determine the penetration of the steroid clobetasol into        human epidermis following topical application of mousse        formulations to which increasing concentrations of petrolatum        had been included as a potential occlusive agent and penetration        enhancer.    -   (2) To assess clobetasol penetration following application to        intact epidermis and that which had been stripped 3 times with        tape to model the impaired stratum comeum barrier function seen        in the dermatological conditions for which the drug is used        clinically.        Method

Preparation of epidermal membranes: Donated human female abdominal skinwas separated by blunt dissection, to remove subcutaneous fat andextraneous tissue, and immersed in water at 60° C. for 2 minutes toallow separation of the epidermal-dermal junction. Epidermal membraneswere lifted from the dermis by gently rolling from one end with thefingers and stored on filter paper, stratum comeum uppermost, at −20° C.until use.

Diffusion Studies Epidermal membranes were mounted, stratum comeumuppermost and facing the donor chamber, on filter paper between the twohalves of standard horizontal glass Franz-type diffusion cells (areaapprox. 1.3 cm²). The bottom half of the diffusion cells was filled withapproximately 3.5 ml of receptor medium (either 20% ethanol in distilledwater for intact epidermal membrane studies or Baxter 20% Intralipid®solution for stripped skin studies) and continuously stirred with smallmagnetic fleas. Assembled cells were semi-submerged in a water bathmaintained at 35±0.1° C.

Mousse formulations containing 0.05% clobetasol with the inclusion of 0,30 or 50% petrolatum were gently applied to the donor chamber with around-ended plastic rod which was wiped around the skin surface suchthat the skin was covered by a total dose of approximately 10 mg/cm².The weight of formulation applied was verified from the difference inweight of the application rod and small weigh boat from which theformulation had been applied before and after dosing.

Clobetasol was allowed to penetrate into the epidermis for 72 hrs. afterwhich time the remaining formulation was removed from the skin surfaceby washing and a single tape strip was performed to ensure that minimal.‘unpenetrated’ material remained on the surface of the epidermis. Allwashes and tape strips were retained for quantification of clobetasolconcentration. The area of epidermis exposed to the formulation was thenremoved from the membrane using a stainless steel punch which wascleaned with methanol between samples to avoid any cross contaminationof clobetasol. Epidermal, tape and wash samples were all assayed forclobetasol concentration by high performance liquid chromatography.

Results

FIG. 1 shows the fraction of the applied amount of clobetasol that wasfound to have penetrated into the epidermal membranes during the study.It can be clearly seen that inclusion of petrolatum in the mousseformulations has increased the amount of clobetasol penetrating into theepidermis of both intact and stripped skin samples. The recovery of theapplied amounts of clobetasol in the washes, tape strip and epidermiswas greater than 75% in all cases.

Conclusion

Increasing concentrations of petrolatum in topical mousse formulationscontaining 0.05% clobetasol was able to increase the in-vitro humanepidermal penetration of the steroid in both intact and stripped skinmodels.

Example 3a The Effect of Petrolatum Concentration on the Occlusivity ofTopical Mousse Formulations

Aim

The aim of the study was to determine whether increasing theconcentration of petrolatum in topical mousse formulations couldeffectively occlude the underlying skin and thereby lead to increasedlocal hydration which in turn is known to improve the percutaneouspenetration of suitable drugs.

Method

Relative degrees of occlusion of the skin in humans can be effectivelyquantified by following changes in the normal rate of transepidermalwater loss (TEWL) caused by procedures such as formulation application.In the present study a commercially available single probe TEWL meter(Tewameter, Courage and Khazaka, Cologne, Germany) was used to determinethe rate of TEWL (g/hr/m²) at a number of 2×2 cm numbered test squaresmarked on the medial side of the forearm of a healthy volunteer.Baseline readings of TEWL were taken in triplicate at each test siteprior to the application of mousse formulation at a dose of 10 mg/cm²containing 0, 10, 20, 30, 40 or 50% petrolatum. To ensure that the doserate of 10 mg/cm² was maintained for each formulation, approximately40mg of each mousse was weighed out onto a 2 cm wide glass slide whichwas then used to wipe the mousse evenly across each one of the markedtest squares before being reweighed to determine the total amount ofmousse transferred onto the skin.

At 30 and 120 minutes following mousse application determinations ofTEWL were repeated at each of the test sites. Relative changes in TEWLwere then calculated by dividing the rate of TEWL following applicationby that taken from the same marked square at t=0.

Results

FIG. 2 shows the actual rate of TEWL (g/hr/m²) determined at each of thetest sites prior to treatment and again at 30 and 120 minutes aftermousse application. A decrease in the rate of TEWL was observed withIncreasing concentrations of petrolatum in the mousse formulations atboth 30 and 120 minutes following application. FIG. 2 clearly shows therelationship between the % of petrolatum content in each of the testmousses and the resultant relative change in the rate of TEWL determinedat 30 and 120 minutes after formulation application.

Conclusion

Increasing the concentration of petrolatum in topical mousseformulations was able to decrease the normal rate of TEWL on the forearmof a healthy volunteer. The decreases in the rate TEWL observedeffectively demonstrate that increasing the concentration of petrolatumin the product leads to an increase in the relative occlusivity of thetopical mousse formulations tested.

Example 3b

Part 2

Aim

The aim of the second part of this study was to assess the degree ofocclusivity afforded by the 50% petrolatum mousse formulation in anumber of healthy volunteers.

Method

The effect of a 10 mg/cm² dose of 50% mousse formulation on the normalrate of TEWL was determined on the forearm of 6 volunteers in a manneridentical to that described above. The relative changes observed in therate of TEWL at 30 and 120 min after application were then compared toan untreated control site measured at the same time on the testedforearm of each volunteer.

Results

FIG. 4 shows the relative rates of TEWL determined at the 2 test siteson the forearms of the volunteers. Significant decreases in TEWL(P<0.05, ANOVA and Students t-test) were observed at both the 30 and 120min post-treatment tests following application of the 50% petrolatummousse formulation. No significant difference was observed in the rateof TEWL between the control sites over the 120 min test period (P=0.19,ANOVA).

Conclusion

Application of a mousse formulation containing 50% petrolatum at a doseof 10 mg/cm² significantly occluded the skin as determined by decreasesin the rate of TEWL observed on the forearms of 6 healthy volunteers.

Finally, it is to be understood that various alterations, modificationsand/or additions may be made without departing from the spirit of thepresent invention as outlined herein.

1. A method for increasing skin permeability of an active agent, saidmethod comprising: applying a topical mousse composition comprising (a)an occlusive agent; (b) an aqueous solvent; (c) an organic cosolvent;and (d) an active agent, wherein the occlusive agent is present in anamount sufficient to form an occlusive layer on the skin to increaseskin permeability of said active agent.
 2. A method for reducing transepidermal water loss with the topical application of an active agent,said method comprising: applying a topical mousse composition comprising(a) an occlusive agent; (b) an aqueous solvent; (c) an organiccosolvent; and (d) an active agent, where after application of saidcomposition, trans epidermal water loss is reduced.
 3. A method fortopical application of an active agent, said method comprising: applyinga topical mousse composition comprising (a) an occlusive agent; (b) anaqueous solvent; (c) an organic cosolvent; and (d) an active agent. 4.The method according to claims 1 or 2 or 3, wherein the occlusive agentcomprises petrolatum.
 5. The method according to claims 1 or 2 or 3,wherein the occlusive agent further comprises a mineral oil and a longchain acid.
 6. The method according to claims 1 or 2 or 3, wherein theocclusive agent is selected from the group consisting of a mineral oiland grease, a long chain acid, an animal fat and grease, a vegetable fatand grease, and a water insoluble polymer.
 7. The method according toclaim 6, wherein the occlusive agent is an animal fat or animal grease.8. The method according to claims 1 or 2 or 3 wherein the occlusiveagent is present in an amount of approximately 55% by weight or less,based on the total weight of the composition.
 9. The method according toclaim 8, wherein the occlusive agent is present in an amount ofapproximately 10 to 50% by weight, based on the total weight of thecomposition.
 10. The method according to claims 1 or 2 or 3, furthercomprising an effective amount of an emulsifier component.
 11. Themethod according to claim 10, wherein the emulsifier component ispresent in an amount of from approximately 1% to 15% by weight, based onthe total weight of the composition.
 12. The method according to claim11, wherein the emulsifier component is present in an amount of fromapproximately 2% to 5% by weight, based on the total weight of thecomposition.
 13. The method according to claim 10, wherein theemulsifier component is selected from the group consisting of anon-ionic surfactant, a cationic surfactant, an anionic surfactant, afatty alcohol, a fatty acid, and fatty acid salts thereof.
 14. Themethod according to claim 10, wherein the emulsifier component comprisesa mixture of a sorbitan ester and a polyoxyethylene fatty alcohol ether.15. The method according to claim 10, wherein the emulsifier componentcomprises a fatty alcohol, a fatty acid or a fatty acid salt.
 16. Themethod according to claims 1 or 2 or 3, wherein the aqueous solvent ispresent in an amount of approximately 25 to 95% by weight, based on thetotal weight of the composition.
 17. The method according to claims 1 or2 or 3, wherein the organic cosolvent is present in an amount ofapproximately 0.25% by weight to 50% by weight, based on the totalweight of the composition.
 18. The method according to claim 17, whereinthe organic cosolvent is present in an amount of approximately 0.5% byweight to 2.0% by weight, based on the total weight of the composition.19. The method according to claims 1 or 2 or 3, wherein the organiccosolvent comprises an ester of a fatty acid.
 20. The method accordingto claims 1 or 2 or 3, wherein the organic cosolvent is selected fromthe group consisting of a medium to long chain alcohol, an aromaticand/or alkyl pyrollidinone, an aromatic and/or alkyl, and/or cyclicketone, an aromatic and/or alkyl, and/or cyclic ether, substitutedand/or unsubstituted single or multiple ring aromatic, straight chainand/or branched chain and/or cyclic alkane or silicone.
 21. The methodaccording to claims 1 or 2 or 3, further comprising an effective amountof an aerosol propellant.
 22. The method according to claim 21, whereinthe aerosol propellant is a hydrocarbon and is present in an amount ofapproximately 2.5 to 20% by weight, based on the total weight of thecomposition.
 23. The method according to claims 1 or 2 or 3 wherein saidactive agent is selected from the group consisting of an analgesic, anantifungal, an antibacterial, an anesthetic, an antiviral, anantipruritic, an antihistamine, a xanthine, a sex hormone, ananti-inflammatory, and a corticosteroid.
 24. The method according toclaim 23, wherein said active agent is an anti-inflammatory.
 25. Themethod according to claim 23, wherein the active agent is insoluble inwater.
 26. The method according to claim 23, wherein the active agent isinsoluble in the occlusive agent.
 27. The method according to claim 23,wherein the active agent is insoluble in both water and the occlusiveagent.
 28. The method according to claim 23, wherein thepharmaceutically active ingredient is present in an amount of fromapproximately 0.005% by weight to approximately 10% by weight, based onthe total weight of the composition.
 29. The method according to claim23, wherein the pharmaceutically active ingredient is present in anamount of from approximately 0.05% by weight to approximately 1% byweight, based on the total weight of the composition.
 30. The methodaccording to claim 23, wherein said active agent is a corticosteroid.31. The method according to claim 23 or 30, wherein said active agent ismore than one active agent.
 32. The method according to claim 30,wherein said corticosteroid is a member selected from the groupconsisting of betamethasone valerate and clobetasol propionate.
 33. Themethod according to claim 23, wherein said active agent is anantibacterial agent.
 34. The method according to claim 33, wherein saidactive agent is more than one active agent.
 35. The method according toclaims 1 or 2 or 3 wherein said mousse composition further comprises atleast one member selected from the group consisting of a preservative, astabilizer, an antioxidant, a pH adjusting agent, a skin penetrationenhancer, and a viscosity modifying agent.